The goal of this proposed work is to c h a racterize the catalytic and gene regulatory functions of histone deacetylases (HDACs). HDACs regulate the expression of many genes, act in pathways that regulate cell cycle progression and growth, and are implicated in human cancer. Small molecule inhibitors of these enzymes induce growth arrest, differentiation and apoptosis in a variety of tumor cell lines. Nonetheless, the mechanisms by which HDACs regulate transcription remain poorly understood. A simplistic model of HDAC function is that by deacetylating lysines in histone proteins these enzymes induce a more compact chromatin structure that is transcriptionally repressive. A more sophisticated view is that genes can be activated or repressed depending on precisely which lysine residues are deacetylated. Since HDACs are conserved throughout eukaryotes, yeast is an ideal model organism in which to unravel the complexities of these enzymes. The yeast HDACs RPD3 and SIR2 have previously been shown to have opposite effects on silencing and aging. Preliminary results, obtained by transcriptional profiling, reveal that these HDACs also exert opposite influences on the expression of many genes, including ZRT1 and BNA1 (Bernstein et al., PNAS 97, 13708-13). These findings are consistent with a more sophisticated model of HDAC function. The hypothesis that differential deacetylation mediates the disparate effects of RPD3 and SIR2 on the expression of ZRT1, BNA1, and other genes will be tested by biochemical and genomic methods. The candidate is an M.D./Ph.D. with clinical training in pathology who seeks further training in basic research. His long-term goal is to establish and direct an academic research laboratory studying mechanisms of gene regulation. This project should yield valuable insight into the mechanisms that underlie gene regulation and will prepare the applicant for a career as an independent investigator.